The selective accumulation and activation of leukocytes in inflamed tissues contributes to the pathogenesis of inflammatory and autoimmune diseases. Chemokines and their receptors, which belong to a family of seven transmembrane G-protein coupled receptors are involved in the selective accumulation and activation of leukocytes in inflamed tissues, and in the pathogenesis of inflammatory and autoimmune diseases. One such receptor is CCR1 which is a receptor for CC chemokines, such as CCL5 (RANTES) and CCL3 (MIP-1α).
CCR1 is a therapeutic target for a variety of diseases. In vivo studies on mice indicate that CCR1-mediated leukocyte recruitment is important for interstitial inflammation in the kidney and that CCR1 blockade late in renal disease can halt disease progression and improve renal function (J Am Soc Nephrol 15: 1504-1513, 2004). In vivo studies in mice further indicate that CCR1 may translate inflammatory signals into nociceptor stimuli (Proc. Nat. Acad. Sci. 102: 4536-4541, 2005); CCR1 blockade may therefore obtund inflammatory hyperalgesia. Further, an animal model of neutrophil recruitment in response to MIP-1α demonstrates the positive biological and pharmacodynamic activity of CCR1 antagonists (US 2005/0288319 A1).